Rx Irony: Drug Interactions for Pharmacoenhancement

John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD

Published Online: Thursday, February 1, 2007

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Drug interactions usually are
thought of as being a source of
adverse drug events. Interactions
affecting the metabolism of the
object drug often result in elevation of
the object drug's plasma concentrations,
leading to toxicity. This mechanism, however,
can be employed to boost the plasma
concentrations of the object drug to
achieve or maintain therapeutic concentrations
that otherwise would be difficult
to accomplish.

For example, initially procainamide was
available only as an immediate-release
formulation. Because of its short half-life,
procainamide required administration
every 4 to 6 hours to control arrhythmias.
This regimen often led to poor adherence
and loss of rhythm control. It was known
that cimetidine reduced the renal clearance
of procainamide and could increase
the plasma concentrations of both procainamide
and its active metabolite.1,2
Thus, cimetidine occasionally was used
with procainamide to reduce its elimination
and prolong its half-life. Patients taking
cimetidine and procainamide could
reduce the procainamide dosing frequency
to every 8 hours.

Pharmacoenhancement also can be
used to lower the cost of therapy by
reducing the dose of the object drug.
Several authors have suggested that
cyclosporine cost savings could be
obtained by coadministration of diltiazem.3,4 Diltiazem reduces cyclosporine
clearance by 40% to 70% and enables a
similar reduction in the dose of
cyclosporine. This reduction leads to
direct cost savings on cyclosporine that
are greater than the additional cost
incurred with the addition of diltiazem.

Most recently, several HIV treatment
regimens have utilized pharmacoenhancement
to change the pharmacokinetic
profile of one or more protease
inhibitors.5,6 Lopinavir is a protease
inhibitor that, when administered alone,
has such low bioavailability that it is
unable to produce antiviral concentrations
in the plasma. By combining
lopinavir with a low dose of ritonavir, the
bioavailability of lopinavir is increased
and the drug is able to achieve antiviral
efficacy. The dose of ritonavir is too low
to be of value as an antiviral, but it is adequate
to inhibit the intestinal and hepatic
CYP3A4 metabolism of lopinavir.
Ritonavir also may be inhibiting the P-glycoprotein-mediated efflux of lopinavir.

In addition, ritonavir has been used to
boost the effects of other protease
inhibitors, including saquinavir, indinavir,
and amprenavir. Ritonavir increases the
area under the plasma concentration
time curves, minimum plasma concentration
(Cmin), and half-life. By increasing
the Cmin and half-life, the protease
inhibitor can be administered at less frequent
intervals and still maintain adequate
concentrations to inhibit viral replication.
The patient benefits by having
fewer pills to take less frequently.

Pharmacoenhancement can be associated
with its own risks. The precipitant
drug may have to be administered in a
dose that not only inhibits the elimination
of the object drug, but also may produce
its own side effects. When diltiazem is
used as an enhancer of cyclosporine,
patients may manifest hypotension,
bradycardia, or constipation. The enhancer
usually is a potent inhibitor and may
unintentionally inhibit other object drugs,
leading to unwanted adverse effects. If
the dose of the enhancer is not carefully
adjusted, inadequate or excess increases
in object drug concentrations can occur.

Of course, it is very important for the
patient to adhere to the prescribed drug
regimens for both the object drug and
the enhancer drug so that a consistent
effect can be maintained. Because of the
need for a consistent effect, the use of
natural inhibitors of drug elimination,
such as grapefruit juice, is discouraged
due to the potential lack of consistency
in inhibition.

The use of drug interactions for the
purpose of pharmacoenhancement is
becoming more common, as more is
learned about the desirable characteristics
of both the enhancer and the object
drugs. The enhancer should produce its
effects on the object drug with a minimum
of its own side effects. If increasing
the object drug's concentration is the
goal, the object drug should produce
added therapeutic benefit but with limited
additional toxicity.

Drs. Horn and Hansten are both professorsof pharmacy at the Universityof Washington School of Pharmacy.For an electronic version of this article,including references if any, visitwww.hanstenandhorn.com.